Various cells and organs in the human body originate from a small group of primitive cells called stem cells. Human cancer cells were also recently found to arise from a group of special stem cells, called cancer stem cells (CSCs). At present, cancer that has spread throughout the body (metastasized) is difficult to treat, and survival rates are low. One major reason for therapeutic failure is that CSCs are relatively resistant to current cancer treatments. Although most mature cancer cells are killed by treatment, resistant CSCs will survive to regenerate additional cancer cells and cause a recurrence of cancer. As opposed to other human stem cells, CSCs have their own unique molecules on their cell surface. This project aims to develop agents that specifically target the unique cell surface molecules of CSCs. These agents will have the potential to eradicate cancer from the very root, i.e., from the stem cells (CSCs) that produce mature cancer cells. In this project, we will develop agents that specifically target leukemia stem cells to determine the feasibility of our approach. Leukemia is the fourth most common cause of cancer death in males and the fifth in females. If our approach is successful, we can use the same approach for other cancer types. To develop these specific agents, we will screen a library of billions of molecules to identify those that specifically target the unique cell surface molecules of leukemia stem cells (LSCs). After we identify these specific molecules, we will optimize their structure to increase their specific binding to LSCs. Specific binding to LSCs is crucial, as the optimized molecules will be able to uniquely kill LSCs and spare normal blood cells.
Many leukemia patients need stem cell transplantation during treatment. There are two approaches to harvesting stem cells for transplantation: those harvested from patients themselves and those harvested from healthy donors. Stem cells harvested from healthy donors need to genetically match patients’ cells. Otherwise, these transplanted cells from the donor recognize the recipient’s (host or patient) cells as non-self cells and attack these cells. This response leads to a serious disease called graft-versus-host disease (GVHD). It is often difficult to find matched donors. Stem cells harvested from patients are usually not used for the treatment of acute leukemia because they are contaminated with LSCs that will lead to recurrence of leukemia after transplantation. If this project is successful, the targeting agents developed in this project can be used to eliminate the contaminating LSCs and decrease the leukemia recurrence after transplantation.

Statement of Benefit to California:

Acute leukemia is the sixth most common cause of cancer death in males and females in California. The outcome for acute leukemia is poor and over 70% of patients will die from this disease. This project aims to develop therapeutic agents that specifically target leukemia stem cells and therefore eradicate leukemia from its root. These agents can also be used for stem cell transplantation. Many leukemia patients need stem cell transplantation during treatment. There are two approaches to harvesting stem cells for transplantation: those harvested from patients themselves and those harvested from healthy donors. Stem cells harvested from healthy donors need to genetically match patients’ cells. Otherwise, these transplanted cells from the donor recognize the recipient’s (host or patient) cells as non-self cells and attack these cells. This response leads to a serious disease called graft-versus-host disease (GVHD). It is often difficult to find matched donors. This is especially true in California because of the genetically diversified population. Stem cells harvested from patients are usually not used because they are contaminated with leukemia stem cells that will lead to recurrence of leukemia after transplantation. If this project is successful, the targeting agents developed in this project can be used to eliminate the contaminated leukemia cells and decrease the likelihood of leukemia recurrence after transplantation.
The ligands developed in this project can be used for targeted therapy for leukemia. Since no such ligands have been identified so far that specifically target leukemia stem cells, these ligands can be patented and eventually commercialized. This may have huge financial benefits to California. If this project is successful, the same approach can be used to treat other cancers and for the development of more commercialized drugs.
If this grant is funded, it will secure my career as a physician-scientist in stem cell and cancer research. The physician-scientist is a diminishing breed in that it is difficult for physicians to do research while meeting the huge demands of the clinic. However, there is a huge gap between basic research and clinical applications. This gap is in part traced to the fact that it is difficult to find researchers who know and can integrate clinical needs with basic research. I consider myself a promising physician-scientist who has received extensive, rigorous and systematic training in medical science and basic research ([REDACTED]). If this grant is funded, I will not only carry out this important research, but this will also give me protected time for this research.

Progress Report:

Human cancer cells were recently found to arise from a group of special stem cells, called cancer stem cells (CSCs). At present, cancer that has spread throughout the body (metastasized) is difficult to treat, and survival rates are low. One major reason for therapeutic failure is that CSCs are relatively resistant to current cancer treatments. Although most cancer cells are killed by treatment, resistant CSCs will survive to regenerate additional cancer cells and cause a recurrence of cancer. As opposed to other human stem cells, CSCs may have some unique molecules that can be targeted for cancer treatment. This project is to use such technologies as our patented one-bead one-compound technology (OBOC) to develop small molecules that can specifically target cancer stem cells. With OBOC, trillions copies of small molecules are synthesized in tiny beads around 90 microns. During development, millions of molecules can be screened against cancer stem cells with hours to days. So far, we have identified six molecules that target CSC. Currently, we are optimizing these molecules to increase their efficiency of these molecules on CSC. Once fully developed, these molecules will have the potential to eradicate cancer from the very root, i.e., from the stem cells (CSCs) that produce mature cancer cells.

Acute myeloid leukemia is a group of serious blood malignant diseases. The treatment outcome is poor, in large part, to the fact that a small group of cells named leukemia stem cells can survive treatment, regenerate more leukemic cells and cause recurrence. This project aims to improve the treatment outcomes of acute leukemia by eradicating leukemia stem cells. During the previous two years, we identified several small molecules that can specifically bind to leukemia stem cells. Over the last one year, we determined that one of these small molecules has the potential to work like a “smart missile” to guide the delivery of chemotherapeutic drugs to leukemia stem cells. More specifically, we linked this small molecule on the surface of nanoparticles that are small particles with the size of about 1/100th of one micron (much smaller than the width of a human hair). Inside of these nanoparticles, we can load chemotherapeutic drugs. We found that our small molecules can specifically attach the nanoparticles to leukemia stem cells, and deliver the drug load to the inside of the cells. Therefore, these “smart” nanoparticles can potentially target leukemia stem cells, and eradicate leukemia from the very root. Furthermore, chemotherapeutic drugs formulated in these nanoparticles are less toxic, suggesting that high-dose chemotherapeutic drugs can be given to patients to treat leukemia without increasing the horrendous toxicity associated with regular chemotherapy.

Acute myeloid leukemia is a group of serious blood malignant diseases. The treatment outcome is poor, in large part, due to the fact that a small group of cells named leukemia stem cells can survive treatment, regenerate more leukemic cells and cause recurrence. This project aims to improve the treatment outcomes of acute leukemia by eradicating leukemia stem cells. We identified one molecule that can specifically bind to leukemia stem cells. We also developed nanoparticles that are small particles with the size of about 1/100th of one micron (much smaller than the width of a human hair). Inside of these nanoparticles, we can load chemotherapeutic drugs, such as daunorubicin that is one of the two drugs used for the upfront treatment of acute leukemia. When we attached the stem cell-targeting molecules on the surface of nanoparticles, these nanoparticles work like “small missiles” that can seek and delivery daunorubicin into leukemia stem cells. We have shown that these “smart” nanoparticle can delivery chemotherapeutic drug daunorubicin to leukemia cells directly isolated from clinical patient specimens, and kills these cells more efficient that the regular nanoparticles. Therefore, these “smart” nanoparticles can potentially target leukemia stem cells, and eradicate leukemia from the very root. Furthermore, chemotherapeutic drugs formulated in these nanoparticles are less toxic, suggesting that high-dose chemotherapeutic drugs can be given to patients to treat leukemia without increasing the horrendous toxicity associated with regular chemotherapy.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and a very serious disease. Most AML cells arise from a group of special stem cells, named leukemia stem cells (LSCs). One major reason for treatment failure is that LSCs are relatively resistant to current treatments. Although most leukemia cells are killed by treatment, resistant LSCs will survive to regenerate additional leukemia cells and cause a recurrence of leukemia. Recently, we have developed a small molecule that can recognize and bind to AML LSCs. We have also developed tiny particles named nanomicelles. These nanomicelles have a size of about 1-2/100th of one micron (one millionth of a meter), and can be loaded with chemotherapy drug called daunorubicin that can kill LSCs. In this project, we will coat the drug-loaded nanomicelles with small molecules that specifically bind and kill LSCs. In patient’s body, these drug-loaded nanomicelles will work like “smart bombs”, and deliver a high concentration of daunorubicin to kill LSCs. Over the last one year, we found that these LSC-targeting nanomicelles could target and kill LSC more efficiently that free daunorubicin or nanomicelles that do not target LSC. We also found that, compared to free daunorubicin commonly used in the treatment of AML now, daunorubicin in nanomicelles could raise the blood daunorubicin concentration by more than 20 times. This is clinically significant as leukemia cells and LSC are located inside blood vessels and bone, and have direct contact with blood. Therefore, increase in blood daunorubicin concentration may represent more efficiency in killing leukemia and LSC.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and a very serious disease. Most AML cells arise from a group of special stem cells, named leukemia stem cells (LSCs). One major reason for treatment failure is that LSCs are relatively resistant to current treatments. Although most leukemia cells are killed by treatment, resistant LSCs will survive to regenerate additional leukemia cells and cause a recurrence of leukemia. Recently, we have developed a small molecule that can recognize and bind to AML LSCs. We have also developed tiny particles named nanomicelles. These nanomicelles have a size of about 1-2/100th of one micron (one millionth of a meter), and can be loaded with chemotherapy drug called daunorubicin that can kill LSCs. In this project, we will coat the drug-loaded nanomicelles with small molecules that specifically bind and kill LSCs. In patient’s body, these drug-loaded nanomicelles will work like “smart bombs”, and deliver a high concentration of daunorubicin to kill LSCs. Over the last one year, we found that daunorubicin-loaded nanomicelles could significantly increase the blood daunorubicin concentration by 20-35 times after intravenous administration. This is clinically significant as leukemia cells and leukemia stem cells are mainly located inside blood vessels. Therefore, increase in blood daunorubicin concentration by nanomicelles means leukemia and leukemia stem cells are exposed to 20-35 times more daunorubicin than regular chemotherapy. one of the major toxicity of daunorubicin is toxicity to the heart. As acute myeloid leukemia usually occurs in elderly patients, many of them already have heart diseases that prevent them from receiving the most effective chemotherapeutic drug daunorubicin. We found that, when compared to the standard daunorubicin, daunorubicin in nanomicelle has 3-5 folds less toxicity to the heart. In addition, the toxicity to other vital organs, such as liver and spleen, is significantly decreased. Compared to the standard daunorubicin, daunorubicin in nanomicelles dramatically increases the drug efficacy in killing cancer cells and prolonging the survival in animal models.